A new four-drug combination is highly effective and safe in patients with newly diagnosed multiple myeloma, according to data from the Advance Clinical trial which will be presented at the annual meeting of the American Society of Clinical Oncology, held May 30 through June 3, 2025 in Chicago, Illinois.
The Advance study, led by Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, is a randomized, multi-center trial tests the effects of adding the targeted drug daratumumab (Darzalex®; Johnson & Johnson) to the standard three-part therapy regimen, called KRd whicj includes carfilzomib (Kyprolis®; Amgen), lenalidomide (Revlimid®; Celgene Corporation, a Bristol Myers Squibb company) and dexamethasone, (Decadron®; Merck & Co/MSD).
“This study shows that daratumumab added to KRd is a new standard of care for those patients who had previously been candidates for just KRd,” explained Sylvester Myeloma Institute Director and study head C. Ola Landgren, M.D., Ph.D., who will present the findings June 3, 2025.
From MANHATTAN to ADVANCE
The new clinical trial has its roots in the MANHATTAN trial, a smaller trial also led by Landgren. In that trial, newly diagnosed multiple myeloma patients were also treated with daratumumab added to KRd, a combination called DKRd.
The results of the MANHATTAN trial were ‘spectacular,’ Landgren said. “Sensitive methods to assess for minimal residual disease (MRD) showed that 71% of patients had no detectable disease after completing their treatment. That trial, however, was a single-arm study — all 41 patients received DKRd.”
The ADVANCE trial goes further by directly comparing KRd to DKRd in a large, multi-center, randomized (1:1) clinical trial in the U.S.
Improving Outcomes
Half of the 306 patients in the ADVANCE trial were randomly assigned to treatment with KRd and half to DKRd.
The new results show that 59% of DKRd-treated patients were MRD-negative after eight cycles of treatment compared with 36% of KRd-treated patients.
The longer-term durability of the response is an open question. However, the data so far are encouraging: at 32.7 months of follow-up, 86% of patients on DKRd showed progression-free survival, compared to 79% of patients on KRd.
“Adding daratumumab to KRd did not add any significant toxicities,” noted Landgren.
“This is, in part, because of exclusion of patients with underlying cardiovascular disease or patients who were frail. Prior to study enrollment, all patients were screened and cleared by standard labs, a standard clinical exam, and EKG and cardiac ECHO, per the study protocol,” Landgren explained.
“If you give it to the right patients, in the right way, it is an extremely safe and very effective therapy,” said Landgren.
Therapeutic Targets
The new four-drug drug combination leverages a range of therapeutic targets and modalities. Carfilzomib inhibits the protein-degrading machinery in cells, and Lenalidomide stimulates immune activity against tumors, among other actions. Dexamethasone has effects on immunity and inflammation.
“These three drugs may shrink tumors enough to enable daratumumab to finish the job,” said Landgren.
Daratumumab targets the CD38 protein on multiple myeloma cells and induces tumor cell death.
Tumors from patients in the trial are undergoing detailed molecular scrutiny. Questions include why tumors respond differently to the drug regimens, and why some develop resistance.
A New Standard of Care
Newly diagnosed multiple myeloma patients at Sylvester and other cancer centers are already routinely receiving the four-drug DKRd combination.
“It has definitely changed my practice,” noted Sylvester physician Dickran Kazandjian, M.D., lead co-PI on the ADVANCE study.
“Your best shot at getting your best response is with the first treatment,” Kazandjian added,
Changing clinical practice
Landgren’s research has changed clinical practice before. His studies helped lead to the adoption of carfilzomib as a less toxic substitute for bortezomib.
And this time, Landgren and his team may change clinical practice yet again. They are planning a new multiple myeloma trial that will test several drugs in combination with a bispecific T-cell engager, a newer type of immunotherapy treatment.
The ADVANCE trial also showcases a trend in which an increasing number of patients are forgoing up-front transplantation as a consequence of achieving MRD negativity with modern, effective combination therapy alone.
Eligible patients in the study had stem cells collected after four cycles, in case they need a transplant after completing treatment. But the patients who achieved MRD-negative status kept their stem cells in the -80°C freezer and deferred their transplant. Instead, they moved straight to lenalidomide maintenance therapy, per the study protocol.
Landgren and Kazandjian credit the Sylvester clinical trial team for bringing the ADVANCE study to Sylvester locations throughout south Florida. Other institutions involved in the ADVANCE trial are MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Moffitt Cancer Center, Roswell Park Comprehensive Cancer Center, Huntsman Cancer Foundation and Stony Brook Cancer Center.
The National Cancer Institute estimates that 36,110 people in 2025 will be newly affected by multiple myeloma, the second most common blood cancer.
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Clinical trials
A Study of Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly-Diagnosed Multiple Myeloma (ADVANCE) – ClinicalTrials.gov ID NCT04268498
Highlights of prescribing information
Daratumumab (Darzalex®; Johnson & Johnson)[Prescribing Information]
Carfilzomib (Kyprolis®; Amgen)[Prescribing Information]
Lenalidomide (Revlimid®; Celgene Corporation, a Bristol Myers Squibb company)[Prescribing Information]
Dexamethasone (Decadron®; Merck & Co/MSD) [Prescribing Information]
Reference
[1] Carl Landgren, Jing Ye, Jens Hillengass, Douglas Sborov, James Hoffman, Benjamin Diamond, David Coffey, Marcella Kaddoura, Abhishek Pandey, Kellye Koubek, Stephanie Mompoint, Sindy Gutierrez, Caterine Diaz, Michelle Armogan, Rachid Baz, Robert Orlowski, Thomas Jandl, Neha Korde, Kenneth Shain, Dickran Kazandjian. Randomized, multi-center study of carfilzomib, lenalidomide, and dexamethasone (KRd) with or without daratumumab (D) in patients with newly diagnosed multiple myeloma (NDMM): The ADVANCE clinical trial. JCO, 10.1200/JCO.2025.43.16_suppl.7503
Featured image: “This study shows that daratumumab added to KRd is a new standard of care for those patients who had previously been candidates for just KRd,” said C. Ola Landgren, M.D., Ph.D., director of the Myeloma Institute at Sylvester Comprehensive Cancer Center. Photo cour by Sylvester Cancer
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